Plasma endocannabinoids in cocaine dependence and their relation to cerebral metabotropic glutamate receptor 5 density.

Animal models indicate that the endocannabinoid system (ECS) plays a modulatory role in stress and reward processing, both crucially impaired in addictive disorders. Preclinical findings showed endocannabinoid-modulated synaptic plasticity in reward brain networks linked to the metabotropic-glutamate-5 receptor (mGluR5), contributing to drug-reinforcing effects and drug-seeking behavior. Although animal models postulate a link between ECS and cocaine addiction, human translational studies are lacking. Here, we tested previous preclinical findings by investigating plasma endocannabinoids (eCBs) anandamide (AEA), 2-arachidonoylglycerol (2-AG), and the related N-acylethanolamines (NAEs) palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), including their interaction with cerebral mGluR5, in chronic cocaine users (CU). We compared basal plasma concentrations between chronic CU (N = 103; 69 recreational CU and 34 dependent CU) and stimulant-naïve healthy controls (N = 92). Follow-up basal eCB/NAE plasma levels after 12 months were used for reliability and stability check (CU: N = 33; controls: N = 43). In an additional analysis using 11C-ABP688 positron emission tomography (PET) in a male subsample (CU: N = 18; controls: N = 16), we investigated the relationships between eCBs/NAEs and mGluR5 density in the brain. We found higher 2-AG plasma levels in dependent CU compared to controls and recreational CU. 2-AG levels were stable over time across all groups. In the PET-subsample, a positive association between 2-AG and mGluR5 brain density only in CU was found. Our results corroborate animal findings suggesting an alteration of the ECS in cocaine dependence and an association between peripheral 2-AG levels and cerebral mGluR5 in humans. Therefore, the ECS might be a promising pharmaco-therapeutic target for novel treatments of cocaine dependence.

Social and Non-Social Cognitive Enhancement in Cocaine Users-A Closer Look on Enhancement Motives for Cocaine Consumption.

BACKGROUND: Cognitive disturbances of chronic cocaine users (CU) have been repeatedly investigated. However, it is yet unknown how CU using cocaine for cognitive or social enhancement differ from stimulant-naïve controls and CU that do not have these motives. More precisely, we assumed that CU with an enhancement motive self-medicate deficits in specific cognitive abilities, i.e., they use cocaine to enhance their performance in either social (social motive) or non-social cognitive situations (cognitive motive). METHODS: Forty-two CU were categorized according to their motives for cocaine consumption into social and non-social motive groups as well as cognitive and non-cognitive motive groups, respectively. Subsequently, CU motive groups were compared to 48 stimulant-naïve controls in their social and non-social cognitive functioning applying a comprehensive neuropsychological test battery. RESULTS: The social motive group showed deficits in cognitive empathy compared to controls (Cohen's d = 0.65) and the non-social motive group (d = 0.60). No mentionable effects were found for emotional empathy and Theory-of-Mind. Cognitive and non-cognitive motive groups both showed general cognitive deficits but with different patterns of impairments compared to controls: the cognitive motive group had deficits mainly in working memory (d = 0.84) and declarative memory (d = 0.60), whereas the non-cognitive motive group also had deficits in working memory (d = 0.61) but additionally in executive functions (d = 0.67). For the domains declarative memory and executive functions, the respective other CU group displayed intermediate performance. CONCLUSIONS: This study demonstrates that cocaine is partially instrumentalized by CU with specific enhancement motives to counteract related cognitive impairments.

Is (poly-) substance use associated with impaired inhibitory control? A mega-analysis controlling for confounders.

Many studies have reported that heavy substance use is associated with impaired response inhibition. Studies typically focused on associations with a single substance, while polysubstance use is common. Further, most studies compared heavy users with light/non-users, though substance use occurs along a continuum. The current mega-analysis accounted for these issues by aggregating individual data from 43 studies (3610 adult participants) that used the Go/No-Go (GNG) or Stop-signal task (SST) to assess inhibition among mostly "recreational" substance users (i.e., the rate of substance use disorders was low). Main and interaction effects of substance use, demographics, and task-characteristics were entered in a linear mixed model. Contrary to many studies and reviews in the field, we found that only lifetime cannabis use was associated with impaired response inhibition in the SST. An interaction effect was also observed: the relationship between tobacco use and response inhibition (in the SST) differed between cannabis users and non-users, with a negative association between tobacco use and inhibition in the cannabis non-users. In addition, participants' age, education level, and some task characteristics influenced inhibition outcomes. Overall, we found limited support for impaired inhibition among substance users when controlling for demographics and task-characteristics.

Improvement of Emotional Empathy and Cluster B Personality Disorder Symptoms Associated With Decreased Cocaine Use Severity.

Aims: Chronic cocaine users display impaired social cognitive abilities, reduced prosocial behavior, and pronounced cluster B personality disorder (PD) symptoms all contributing to their social dysfunctions in daily life. These social dysfunctions have been proposed as a major factor for maintenance and relapse of stimulant use disorders in general. However, little is known about the reversibility of social cognitive deficits and socially problematic personality facets when stimulant use is reduced or ceased. Therefore, we examined the relation between changing intensity of cocaine use and the development of sociocognitive functioning and cluster B PD symptomatology over the course of 1 year. Methods: Social cognition, social decision-making, and cluster B PD symptoms were assessed in 38 cocaine users (19 with increased and 19 with decreased use) and 48 stimulant-naive healthy controls at baseline and at 1-year follow-up. Cocaine use severity was objectively determined by quantitative 6-month hair analyses. The categorization of the two cocaine user groups was based on a combination of absolute (± 0.5 ng/mg) and relative (± 10%) changes in the cocaine hair concentration between baseline and the 1-year follow-up. Social cognition was assessed using the Multifaceted Empathy Test (MET) and the Movie for the Assessment of Social Cognition (MASC). A combined Distribution/Dictator Game was applied for assessing social decision-making. Cluster B PD symptoms were measured by a Structured Clinical Interview for DSM-IV Axis II Disorders (SCID-II) PD questionnaire according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). Results: Increased cocaine use was linked to worsened empathy, while decreased cocaine use went along with improved emotional empathy. Moreover, whereas decreased cocaine use was associated with reduced severity of self-reported cluster B PD symptoms, these symptoms remained largely stable in increasers. In contrast to a significant reduction of prosocial behavior at baseline in the combined cocaine user group, specifically decreasers were not statistically distinguishable from controls at the follow-up. Conclusions: Sociocognitive deficits and cluster B PD symptoms of chronic cocaine users are adaptable over time as they covary with the increase or decrease in cocaine use. Hence, abstinence orientation and training of social cognition and interaction might improve social functioning, and should therefore be important therapeutic elements in cocaine addiction treatment.

Longitudinal changes in cocaine intake and cognition are linked to cortical thickness adaptations in cocaine users.

BACKGROUND: Cocaine use has been consistently associated with decreased gray matter volumes in the prefrontal cortex. However, it is unclear if such neuroanatomical abnormalities depict either pre-existing vulnerability markers or drug-induced consequences. Thus, this longitudinal MRI study investigated neuroplasticity and cognitive changes in relation to altered cocaine intake. METHODS: Surface-based morphometry, cocaine hair concentration, and cognitive performance were measured in 29 cocaine users (CU) and 38 matched controls at baseline and follow-up. Based on changes in hair cocaine concentration, CU were classified either as Decreasers (n = 15) or Sustained Users (n = 14). Surface-based morphometry measures did not include regional tissue volumes. RESULTS: At baseline, CU displayed reduced cortical thickness (CT) in lateral frontal regions, and smaller cortical surface area (CSA) in the anterior cingulate cortex, compared to controls. In Decreasers, CT of the lateral frontal cortex increased whereas CT within the same regions tended to further decrease in Sustained Users. In contrast, no changes were found for CSA and subcortical structures. Changes in CT were linked to cognitive performance changes and amount of cocaine consumed over the study period. CONCLUSIONS: These results suggest that frontal abnormalities in CU are partially drug-induced and can recover with decreased substance use. Moreover, recovery of frontal CT is accompanied by improved cognitive performance confirming that cognitive decline associated with cocaine use is potentially reversible.

Glucocorticoid receptor gene variants and lower expression of NR3C1 are associated with cocaine use.

Animal and cross-sectional human studies suggest that chronic cocaine use is associated with altered responsivity of the hypothalamic-pituitary-adrenal axis to stress. Moreover, increased susceptibility to stress has been proposed as an important factor for development, maintenance and relapse of cocaine addiction. As the glucocorticoid receptor gene (NR3C1) mediates genomic effects of the stress hormone cortisol, we investigated NR3C1 expression and the association of NR3C1 genotypes with cocaine use, addiction and comorbid psychiatric symptoms in 126 chronic cocaine users and 98 stimulant-naïve healthy controls. A comprehensive psychiatric assessment was performed including severity of depressive symptoms and current psychological distress. Whole blood NR3C1 mRNA levels were determined and six NR3C1 polymorphisms (rs10482605, rs41423247, rs10052957, rs6189, rs56149945 and rs6198) were genotyped. Compared to controls, cocaine users showed significantly lower NR3C1 expression (P < 0.001), which was not affected by NR3C1 genotypes. In controls, rs41423247 [P < 0.01, false discovery rate (FDR)-corrected], haplotype 2 and haplotype 3 (both P < 0.05, FDR-corrected) were associated with altered NR3C1 gene expression. Haplotype 3 (including minor alleles of rs10052957 and rs41423247) was associated with an increased risk for cocaine addiction (odds ratio = 2.74, P < 0.05, uncorrected). Moreover, addicted cocaine users carrying haplotype 3 showed higher depression scores (P < 0.01, FDR-corrected) than noncarriers. Considering possible confounding effects of alcohol and/or depression, we conclude that chronic cocaine use is associated with lower NR3C1 gene expression suggesting possible direct effects of the drug on the biological adaptation of stress-related genes. Finally, we postulate that haplotype 3 of NR3C1 might serve as a potential risk factor for stimulant addiction and associated psychiatric symptoms.

Cognitive and neuroanatomical impairments associated with chronic exposure to levamisole-contaminated cocaine.

Currently, levamisole is the most common cocaine adulterant worldwide and it is known to induce a variety of adverse side effects. Animal studies and human case reports suggest potential neurotoxicity of the compound but neither neuroanatomical nor cognitive effects of levamisole have been systematically investigated in cocaine users so far. We examined cognitive performance and cortical structural differences between chronic cocaine users with low and high recent exposure to levamisole objectively determined by quantitative toxicological hair analyses. In Study 1, we compared 26 chronic cocaine users with low levamisole exposure (lowLevCU), 49 matched cocaine users with high levamisole exposure (highLevCU), and 78 matched stimulant-naive controls regarding cognitive functioning employing a comprehensive neuropsychological test battery. In Study 2, we investigated cortical thickness by use of T1-weighted MRI in a subgroup of 12 lowLevCU, 17 highLevCU, and 38 stimulant-naive controls. In Study 1, both cocaine user groups showed significant impairments in the cognitive domains of attention and working memory as well as in the global cognitive index. However, highLevCU showed significantly worse executive functions compared to lowLevCU although both groups did not differ in severity of cocaine consumption and other clinical dimensions. Study 2 revealed that highLevCU, displayed reduced cortical thickness specifically in the middle frontal gyrus compared to both controls and lowLevCU. Our results suggest that levamisole exposure during the last months in cocaine users is associated with increased executive function impairments and pronounced thinning of the lateral prefrontal cortex. Consequently, prevention and drug policy-making should aim to reduce levamisole contamination of street cocaine.

Socio-cognitive functioning in stimulant polysubstance users.

BACKGROUND: Using more than one psychotropic substance is accompanied by increased risks for psychiatric and physical disorders. Accordingly, deficits in basal cognitive functions have been consistently associated with polysubstance use (PSU), whereas little is known about potential impairments in more complex socio-cognitive skills, which are relevant for daily-life functioning. Therefore, we investigated the effects of toxicological validated stimulant PSU on social cognition under consideration of potential cumulative effects. METHODS: We compared socio-cognitive performances of 47 individuals with stimulant PSU with 59 matched stimulant-naïve controls using the Multifaceted Empathy Test (MET) and the Movie for the Assessment of Social Cognition (MASC). Additionally, social network size was assessed by the Social Network Questionnaire (SNQ). Hair and urine testing was employed to categorize three PSU subgroups (3, 4, and ≥5 substances used) and to ensure drug abstinence in controls. RESULTS: Individuals with stimulant PSU showed lower emotional empathy (MET) and a smaller social network (SNQ) compared to controls (both with linear trends for increasing number of used substances: p < .05). In contrast, cognitive empathy (MET and MASC) was largely unaffected by PSU. Additional linear regression analyses within PSU individuals revealed number of used substances as the best predictor for inferior performance in emotional empathy (p < .01), while severity of the use of single substances or substance-classes did not show a significant impact. CONCLUSION: These findings demonstrate cumulative adverse effects of stimulant PSU on an important facet of socio-cognitive functioning. Therefore, emotional empathy deficits should be targeted in future interventions and rehabilitations for individuals with PSU.

Social Cognition and Interaction in Chronic Users of 3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy").

Background: The empathogen 3,4-methylenedioxymethamphetamine (MDMA) is the prototypical prosocial club drug inducing emotional openness to others. It has recently been shown that acutely applied 3,4-MDMA in fact enhances emotional empathy and prosocial behavior, while it simultaneously decreases cognitive empathy. However, the long-term effects of 3,4-MDMA use on socio-cognitive functions and social interactions have not been investigated yet. Therefore, we examined emotional and cognitive empathy, social decision-making, and oxytocin plasma levels in chronic 3,4-MDMA users. Methods: We tested 38 regular but recently abstinent 3,4-MDMA users and 56 3,4-MDMA-naïve controls with the Movie for the Assessment of Social Cognition, the Multifaceted Empathy Test, and the Distribution Game and the Dictator Game. Drug use was objectively quantified by 6-month hair analyses. Furthermore, oxytocin plasma levels were determined in smaller subgroups (24 3,4-MDMA users, 9 controls). Results: 3,4-MDMA users showed superior cognitive empathy compared with controls in the Multifaceted Empathy Test (Cohen's d=.39) and in the Movie for the Assessment of Social Cognition (d=.50), but they did not differ from controls in emotional empathy. Moreover, 3,4-MDMA users acted less self-serving in the Distribution Game. However, within 3,4-MDMA users, multiple regression analyses showed that higher 3,4-MDMA concentrations in hair were associated with lower cognitive empathy (ßMDMA=-.34, t=-2.12, P<.05). Oxytocin plasma concentrations did not significantly differ between both groups. Conclusions: We conclude that people with high cognitive empathy abilities and pronounced social motivations might be more prone to 3,4-MDMA consumption. In contrast, long-term 3,4-MDMA use might nevertheless have a detrimental effect on cognitive empathy capacity.

Discrete memory impairments in largely pure chronic users of MDMA.

Chronic use of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") has repeatedly been associated with deficits in working memory, declarative memory, and executive functions. However, previous findings regarding working memory and executive function are inconclusive yet, as in most studies concomitant stimulant use, which is known to affect these functions, was not adequately controlled for. Therefore, we compared the cognitive performance of 26 stimulant-free and largely pure (primary) MDMA users, 25 stimulant-using polydrug MDMA users, and 56 MDMA/stimulant-naïve controls by applying a comprehensive neuropsychological test battery. Neuropsychological tests were grouped into four cognitive domains. Recent drug use was objectively quantified by 6-month hair analyses on 17 substances and metabolites. Considerably lower mean hair concentrations of stimulants (amphetamine, methamphetamine, methylphenidate, cocaine), opioids (morphine, methadone, codeine), and hallucinogens (ketamine, 2C-B) were detected in primary compared to polydrug users, while both user groups did not differ in their MDMA hair concentration. Cohen's d effect sizes for both comparisons, i.e., primary MDMA users vs. controls and polydrug MDMA users vs. controls, were highest for declarative memory (dprimary=.90, dpolydrug=1.21), followed by working memory (dprimary=.52, dpolydrug=.96), executive functions (dprimary=.46, dpolydrug=.86), and attention (dprimary=.23, dpolydrug=.70). Thus, primary MDMA users showed strong and relatively discrete declarative memory impairments, whereas MDMA polydrug users displayed broad and unspecific cognitive impairments. Consequently, even largely pure chronic MDMA use is associated with decreased performance in declarative memory, while additional deficits in working memory and executive functions displayed by polydrug MDMA users are likely driven by stimulant co-use.

Stable self-serving personality traits in recreational and dependent cocaine users.

Chronic cocaine use has been associated with impairments in social cognition, self-serving and antisocial behavior, and socially relevant personality disorders (PD). Despite the apparent relationship between Machiavellianism and stimulant use, no study has explicitly examined this personality concept in cocaine users so far. In the frame of the longitudinal Zurich Cocaine Cognition Study, the Machiavellianism Questionnaire (MACH-IV) was assessed in 68 recreational and 30 dependent cocaine users as well as in 68 psychostimulant-naïve controls at baseline. Additionally, three closely related personality dimensions from the Temperament and Character Inventory (TCI)-cooperativeness, (social) reward dependence, and self-directedness-and the screening questionnaire of the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II) were acquired. At the one-year follow-up, 57 cocaine users and 48 controls were reassessed with the MACH-IV. Finally, MACH-IV scores were correlated with measures of social cognition and interaction (cognitive/emotional empathy, Theory-of-Mind, prosocial behavior) and with SCID-II PD scores assessed at baseline. Both recreational and dependent cocaine users showed significantly higher Machiavellianism than controls, while dependent cocaine users additionally displayed significantly lower levels of TCI cooperativeness and self-directedness. During the one-year interval, MACH-IV scores showed high test-retest reliability and also the significant gap between cocaine users and controls remained. Moreover, in cocaine users, higher Machiavellianism correlated significantly with lower levels of cooperativeness and self-directedness, with less prosocial behavior, and with higher cluster B PD scores. However, Machiavellianism was not correlated with measures of cocaine use severity (r<-.15). Both recreational and dependent cocaine users display pronounced and stable Machiavellian personality traits. The lack of correlations with severity of cocaine use and its temporal stability indicates that a Machiavellian personality trait might represent a predisposition for cocaine use that potentially serves as a predictor for stimulant addiction.

α2A -Adrenergic receptor polymorphisms and mRNA expression levels are associated with delay discounting in cocaine users.

Cocaine users characteristically display preferences for smaller immediate rewards over larger delayed rewards, and this delay discounting (DD) has been proposed as an endophenotype of cocaine addiction. Recent evidence suggests that the norepinephrine system and more specifically the α2A -adrenergic receptor (ADRA2A) are impacted by chronic cocaine use while also being potentially involved in the neural mechanisms underlying DD. Hence, we investigated the effects of ADRA2A polymorphisms and ADRA2A mRNA expression levels on DD of cocaine users and stimulant-naïve controls. Two hundred and twenty-three participants (129 cocaine users and 94 stimulant-naïve healthy controls) completed a computerized DD paradigm and were genotyped for three single nucleotide polymorphisms (SNPs; rs1800544, rs521674 and rs602618) in the ADRA2A gene, while their peripheral ADRA2A mRNA expression was quantified in whole blood samples. The three SNPs were in near-perfect linkage disequilibrium. Accordingly, significant group*genotype interactions were found for all three ADRA2A variants revealing steeper DD in cocaine users (but not in controls) carrying the G-allele of SNP rs1800544, the T-allele of rs521674 and the C-allele of rs602618. Similarly, high ADRA2A mRNA expression levels were significantly associated with a reduced tendency to choose smaller more immediate rewards (over larger delayed rewards) in cocaine users but not in controls. As the relationship between DD and cocaine use was moderated by ADRA2A SNPs and by peripheral ADRA2A gene expression, we propose that the norepinephrine system is involved in DD deficits observed in cocaine using individuals. Consequently, pharmacological compounds targeting ADRA2As might be considered for the symptom-specific treatment of delay aversion in stimulant addiction.

Risky Decisions in a Lottery Task Are Associated with an Increase of Cocaine Use.

Cocaine use disorder is associated with maladaptive decision-making behavior, which strongly contributes to the harmful consequences of chronic drug use. Prior research has shown that cocaine users exhibit impaired neuropsychological test performances, particularly with regard to attention, learning, and memory but also in executive functions such as decision-making and impulse control. However, to what extent cocaine users show impaired decision-making under risk without feedback has not yet been investigated systematically. Therefore, to examine risk-taking behavior, 31 chronic cocaine users and 26 stimulant-naïve healthy controls who were part of the Zurich Cocaine Cognition Study, performed the Randomized Lottery Task (RALT) with winning lotteries consisting of an uncertain and a certain prospect. Results revealed that risky decisions were associated with male sex, increased cocaine use in the past year, higher cocaine concentrations in the hair, and younger age. In addition, higher levels of cocaine in the hair and cumulative lifetime consumption were associated with risky decisions, whereas potentially confounding factors including cognition and psychiatric symptoms had no significant effect. Taken together, our results indicate that cocaine users who increased their consumption over a period of 1 year show deficits in the processing of risky information accompanied with increased risk-taking. Future research should analyse whether risky decisions could potentially serve as a prognostic marker for cocaine use disorder.

Cognitive and emotional impairments in adults with attention-deficit/hyperactivity disorder and cocaine use.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is an important modulator of cognitive and social functioning in cocaine addiction but it is unclear whether ADHD symptoms and cocaine use display mutually aggravating interaction effects on cognition, social functioning, and depressive symptoms. Therefore, we investigated the interaction of cocaine use and adult ADHD on social and non-social cognition and depressive symptoms. METHODS: Twenty-four cocaine users with (CU+ADHD) and 30 without ADHD (CU-ADHD), 29 cocaine-naïve ADHD patients, and 40 cocaine-naïve healthy controls underwent comprehensive neuropsychological testing including assessment of social cognition (cognitive/emotional empathy and Theory-of-Mind). Additionally, depressive symptoms were measured with the Beck Depression Inventory. RESULTS: The effect size of global cognitive impairment was largest in CU+ADHD (d=1.22 vs. controls) followed by CU-ADHD (d=0.74), and cocaine-naïve ADHD patients (d=0.33). A similar pattern appeared regarding depressive symptoms (CU+ADHD: d=1.47; CU-ADHD: d=0.49, ADHD: d=0.34). In the measures of Theory-of-Mind (CU+ADHD: d=0.76; CU-ADHD: d=0.06, ADHD: d=0.01) and cognitive empathy (CU+ADHD: d=0.80; CU-ADHD: d=0.39, ADHD: d=-0.11) only CU+ADHD showed moderate to large impairments. Moreover, two-way analyses of covariance revealed a significant interaction effect of the factors ADHD and cocaine use on depressive symptoms (p<0.05) and Theory-of-Mind (p<0.05) but not on global cognitive performance (p=0.64). CONCLUSIONS: When occurring together, cognitive impairments associated with both ADHD and cocaine use are largely additive, whereas both factors seem to mutually potentiate one another with respect to mood and mental perspective-taking disturbances. Given the high comorbidity between ADHD and cocaine use, longitudinal studies are needed to investigate the origin of these potentiated impairments.

Glutamatergic and neurometabolic alterations in chronic cocaine users measured with (1) H-magnetic resonance spectroscopy.

Cocaine addiction is a chronically relapsing disorder that is associated with harmful consequences. Relapses occur frequently and effective pharmacotherapies are currently sparse. Preclinical studies suggest that altered glutamatergic signaling is crucial for the maintenance of cocaine self-administration. However, the translational validity of these models is currently unknown. Therefore, we investigated potential differences of glutamate, glutamine and further metabolite levels in the pregenual anterior cingulate cortex (pgACC) and the right dorsolateral prefrontal cortex (rDLPFC) of chronic cocaine users and controls using the PRior knOwledge FITting 2.0 tool in combination with two-dimensional J-resolved single-voxel (1) H-magnetic resonance spectroscopy at 3T and voxel tissue composition and relaxation correction. Glutamate and glutamine levels did not differ between cocaine users and controls, but higher weekly cocaine use and higher cocaine hair concentrations were associated with lower glutamine/creatine ratios in the pgACC. Interestingly, cocaine users exhibited higher glucose/total creatine ratios than controls in the pgACC and higher choline/creatine ratios in the pgACC and rDLPFC. These results imply that cocaine use is associated with altered cortical glucose metabolism and membrane turnover. Finally, cocaine use over the past 6 months appears to decrease cortical glutamine levels indicating changes in glutamate cycling.

Pharmacological Cognitive Enhancement in Healthy Individuals: A Compensation for Cognitive Deficits or a Question of Personality?

The ongoing bioethical debate on pharmacological cognitive enhancement (PCE) in healthy individuals is often legitimated by the assumption that PCE will widely spread and become desirable for the general public in the near future. This assumption was questioned as PCE is not equally save and effective in everyone. Additionally, it was supposed that the willingness to use PCE is strongly personality-dependent likely preventing a broad PCE epidemic. Thus, we investigated whether the cognitive performance and personality of healthy individuals with regular nonmedical methylphenidate (MPH) use for PCE differ from stimulant-naïve controls. Twenty-five healthy individuals using MPH for PCE were compared with 39 age-, sex-, and education-matched healthy controls regarding cognitive performance and personality assessed by a comprehensive neuropsychological test battery including social cognition, prosocial behavior, decision-making, impulsivity, and personality questionnaires. Substance use was assessed through self-report in an interview and quantitative hair and urine analyses. Recently abstinent PCE users showed no cognitive impairment but superior strategic thinking and decision-making. Furthermore, PCE users displayed higher levels of trait impulsivity, novelty seeking, and Machiavellianism combined with lower levels of social reward dependence and cognitive empathy. Finally, PCE users reported a smaller social network and exhibited less prosocial behavior in social interaction tasks. In conclusion, the assumption that PCE use will soon become epidemic is not supported by the present findings as PCE users showed a highly specific personality profile that shares a number of features with illegal stimulant users. Lastly, regular MPH use for PCE is not necessarily associated with cognitive deficits.

Serotonin Transporter and Tryptophan Hydroxylase Gene Variations Mediate Working Memory Deficits of Cocaine Users.

Cocaine users consistently develop working memory (WM) impairments but the mediating molecular mechanisms are unknown so far. Recent evidence suggests that the serotonin (5-HT) system is altered by chronic cocaine use, while also being involved in WM processing. Thus, we investigated the effects of genetic variations impacting 5-HT activity and of peripheral 5-HT transporter (5-HTT) mRNA expression on WM performance in cocaine users and stimulant naive controls. Two hundred twenty participants (126 cocaine users, 94 controls) were assessed with visuospatial, spatial, and verbal WM tasks, genotyped for the length polymorphism in the promoter region of the 5-HTT (5-HTTLPR), the variable number of tandem repeats in the second intron of the 5-HTT (VNTR In2), two single-nucleotide polymorphisms (rs4570625 and rs1386497) in the tryptophan hydroxylase-2 (TPH2) gene and quantified for peripheral 5-HTT mRNA expression in whole-blood samples. Several significant gene × environment interactions between 5-HT genotypes and cocaine use on WM emerged: in cocaine users, the long/long (5-HTTLPR), 9+10/9+10 (VNTR In2) and C/C (TPH2 rs1386497) genotypes were risk alleles for WM impairments, whereas in healthy controls these polymorphisms were associated with improved WM performance. Analogously, high 5-HTT mRNA levels were associated with worse executive WM performance in cocaine users but with increased performance in controls. These gene × environment interactions suggest that the 5-HT system has an important role in the development of cognitive deficits in chronic cocaine users. Hence, pharmacological compounds targeting 5-HT neurotransmission might be promising for the treatment of cognitive deficits in cocaine dependence.

Retrospective monitoring of long-term recreational and dependent cocaine use in toenail clippings/scrapings as an alternative to hair.

BACKGROUND: Toenails were assessed as an alternative matrix to hair for retrospective monitoring of cocaine consumption of recreational and dependent users. Results/methodology: Toenail clippings, scrapings and hair samples from recreational and dependent cocaine users were analyzed for cocaine and metabolites. Dependent users displayed significantly higher concentrations in hair and toenail samples compared to recreational users. Cocaine abstinence could be monitored in hair and toenail samples. One postmortem fingernail was analyzed in layers to investigate the cocaine and metabolite concentration profile. Highest concentrations were observed in the dorsal layer, being indicative of contamination. CONCLUSION: Having led to comparable results, toenails may be an alternative for retrospective monitoring of cocaine consumption/abstinence. Hair should remain the first choice for assessment of temporal evidence of drug intake.

Cognitive impairment in cocaine users is drug-induced but partially reversible: evidence from a longitudinal study.

Cocaine users consistently display cognitive impairments. However, it is still unknown whether these impairments are cocaine-induced and if they are reversible. Therefore, we examined the relation between changing intensity of cocaine use and the development of cognitive functioning within 1 year. The present data were collected as part of the longitudinal Zurich Cocaine Cognition Study (ZuCo(2)St). Forty-eight psychostimulant-naive controls and 57 cocaine users (19 with increased, 19 with decreased, and 19 with unchanged cocaine use) were eligible for analysis. At baseline and after a 1-year follow-up, cognitive performance was measured by a global cognitive index and four neuropsychological domains (attention, working memory, declarative memory, and executive functions), calculated from 13 parameters of a broad neuropsychological test battery. Intensity of cocaine use was objectively determined by quantitative 6-month hair toxicology at both test sessions. Substantially increased cocaine use within 1 year (mean +297%) was associated with reduced cognitive performance primarily in working memory. By contrast, decreased cocaine use (-72%) was linked to small cognitive improvements in all four domains. Importantly, users who ceased taking cocaine seemed to recover completely, attaining a cognitive performance level similar to that of the control group. However, recovery of working memory was correlated with age of onset of cocaine use-early-onset users showed hampered recovery. These longitudinal data suggest that cognitive impairment might be partially cocaine-induced but also reversible within 1 year, at least after moderate exposure. The reversibility indicates that neuroplastic adaptations underlie cognitive changes in cocaine users, which are potentially modifiable in psychotherapeutical or pharmacological interventions.

Functional changes of the reward system underlie blunted response to social gaze in cocaine users.

Social interaction deficits in drug users likely impede treatment, increase the burden of the affected families, and consequently contribute to the high costs for society associated with addiction. Despite its significance, the neural basis of altered social interaction in drug users is currently unknown. Therefore, we investigated basal social gaze behavior in cocaine users by applying behavioral, psychophysiological, and functional brain-imaging methods. In study I, 80 regular cocaine users and 63 healthy controls completed an interactive paradigm in which the participants' gaze was recorded by an eye-tracking device that controlled the gaze of an anthropomorphic virtual character. Valence ratings of different eye-contact conditions revealed that cocaine users show diminished emotional engagement in social interaction, which was also supported by reduced pupil responses. Study II investigated the neural underpinnings of changes in social reward processing observed in study I. Sixteen cocaine users and 16 controls completed a similar interaction paradigm as used in study I while undergoing functional magnetic resonance imaging. In response to social interaction, cocaine users displayed decreased activation of the medial orbitofrontal cortex, a key region of reward processing. Moreover, blunted activation of the medial orbitofrontal cortex was significantly correlated with a decreased social network size, reflecting problems in real-life social behavior because of reduced social reward. In conclusion, basic social interaction deficits in cocaine users as observed here may arise from altered social reward processing. Consequently, these results point to the importance of reinstatement of social reward in the treatment of stimulant addiction.